This invention relates to vasopressin antagonists for use in treating pulmonary hypertension. Specifically, this invention relates to the use of conivaptan for treating pulmonary hypertension.
Pulmonary hypertension (PH) is a condition of increased pulmonary vascular resistance and pulmonary arterial pressure which interferes with ventilation-perfusion relationships. PH typically is characterized by increased blood pressure (above 30 mm Hg systolic and 12 mm Hg diastolic) within the pulmonary circulation. There are two subsets of pulmonary hypertension: primary (idiopathic or xe2x80x9cunexplainedxe2x80x9d) and secondary. The secondary form is by far the more prevalent. The most common causes of secondary pulmonary hypertension are heart disease and lung disease. Regardless of the root cause of the pulmonary hypertension, the resistance (precapillary) vessels of the lungs undergo anatomic change that contributes to the progression of pulmonary hypertension. Pulmonary arterial hypertension secondary to acquired heart disease begins with a disorder of the left ventricle that leads to pulmonary venous hypertension followed by pulmonary arterial hypertension.
Arginine vasopressin, also known as antidiuretic hormone (ADH), is synthesized in the magnocellular neurosecretory cells of the paraventricular and supraoptic nuclei of the hypothalamus and stored in the posterior pituitary. There are 2 classes of AVP receptors, V1 and V2. There are 2 subclasses of V1 receptors, namely V1A and V1B. V1A receptors are found in the vasculature, and mediate the pressor response of AVP by increasing the contraction of blood vessels. Recent in vitro studies in the rat suggest that the lung contains the V1A receptor subtype. V1A receptors are also found on platelets, where they mediate platelet aggregation. V1B receptors are located in the anterior pituitary and mediate adrenocorticotropic hormone (ACTH) release. V2 receptors are located in the collecting ducts of the kidney; they are coupled to aquaporine channels and modulate free water clearance. Arginine vasopressin is released into the circulation in response to an increase in plasma osmolality (mediated by osmoreceptors) or a decrease in plasma volume or blood pressure (mediated by baroreceptors). However, there are other stimuli for AVP release, including norepinephrine, angiotensin II, emotion, nausea and vomiting, and fever. Elevated levels of AVP have been reported in patients with cardiac failure, although its pathophysiologic role is unknown.
We have now discovered that the use of a vasopressin antagonist is effective in reducing pulmonary pressures in patients with pulmonary hypertension. A vasopressin antagonist is surprisingly effective in selectively reducing right sided pressures, including right atrial pressure and pulmonary artery systolic pressure, without affecting systemic hemodynamics. The unexpected selectivity of a vasopressin antagonist on pulmonary circulation would confer benefit in patients with pulmonary hypertension of primary or secondary cause. It is therefore an object of this invention to provide a method for treating pulmonary hypertension by administering a vasopressin antagonist.
The invention provides a method for treating pulmonary hypertension using a vasopressin antagonist. The vasopressin antagonist to be employed is any chemical compound that is effective in inhibiting the biological activity of any arginine vasopressin or antidiuretic hormone. Numerous compounds are known to be vasopressin antagonists, and any of such compounds can be utilized in the treatment of pulmonary hypertension according to this invention.
In a preferred embodiment, the vasopressin antagonist to be utilized is a condensed benzazepine compound, such as those described in U.S. Pat. No. 5,723,606, incorporated herein by reference. In a further preferred embodiment, the vasopressin antagonist is an imidazo benzazepine of the Formula I 
wherein R and R5 are hydrogen or lower alkyl;
R1, R2, and R3 independently are hydrogen, halogen, lower alkyl, lower alkoxy, amino, alkylamino, or dialkylamino; and
R4 is hydrogen, phenyl or substituted phenyl, and pharmaceutically acceptable salts thereof.
An especially preferred vasopressin antagonist to be used in accordance with this invention is conivaptan, which is N-[4-(2-methyl-4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-ylcarbonyl)phenyl]biphenyl-2-carboxamide hydrochloride. Conivaptan is also referred to as CI-1025 and YM087, and has the structural formula below 
Other vasopressin antagonists that can be employed according to this invention include the benzoheterocyclic compounds described in U.S. Pat. No. 5,258,510, incorporated herein by reference. Preferred compounds from this class to be used to treat pulmonary hypertension include the following:
5-Dimethylamino-1-[4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Dimethylamino-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl ]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Methylamino-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl ]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Cyclopropylamino-1-[2-chloro-4-(2-methylbenzoylamino)benzoxyl ]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Cyclopropylamino-1-[2-chloro-4-(2-chlorobenzoylamino)benzoxyl ]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Dimethylamino-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl ]-2,3,4,5-tetrahydro-1H-benzazepine;
5-Dimethylamino-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl ]-1,2,3,4-tetrahydroquinoline;
7-Chloro-5-methylamino-1-[4-(2-methylbenzoylamino)benzoxyl ]-2,3,4,5-tetrahydro-1H-benzazepine; and
7-Chloro-5-methylamino-1-[4-(2-chlorobenzoylamino)benzoxyl ]-2,3,4,5-tetrahydro-1 H-benzazepine.
Other vasopressin antagonists that can be employed according to this invention include those described in U.S. Pat. Nos. 5,225,402; 5,258,510; 5,338,755; 5,719,155; and 5,710,150, all of which are incorporated herein by reference. Specific vasopressin antagonists include YM471, OPC-31260, OPC-21268, OPC-41061, SR-121463, SR-49059, VPA-985, CL-385004, FR-161282, JVT-605, VP-339, WAY-140288, and the like.